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Purpose:Tau hyperphosphorylation is a modification frequently observed after brain ischemia which has been related to the aggregation of this protein, with subsequent cytoskeletal damage, and cellular toxicity. The present study tests the hypothesis of using glucosamine, an agent that increases protein O-GlcNAcylation, to decrease the levels of phosphorylation in Tau during ischemia-reperfusion.Material and methods: Transient focal ischemia was artificially induced in male Wistar rats by occlusion of the middle cerebral artery (MCAO) with an intraluminal monofilament. A single dose of intraperitoneal glucosamine of 200 mg/kg diluted in normal saline (SSN) was administered 60 min before ischemia. Histological brain sections were processed using indirect immunofluorescence with primary antibodies (anti-O-GlcNAc and anti pTau-ser 396). The Image J software was used to calculate the immunofluorescence signal intensity.Results: The phosphorylation of Tau at the serine residue 396 had a significant decrease with the administration of glucosamine during ischemia-reperfusion compared with the administration of placebo.Conclusions: These results show that glucosamine can reduce the phosphorylation levels of Tau in rodents subjected to ischemia and cerebral reperfusion, which implies a neuroprotective role of glucosamine.
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Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Masculino , Glucosamina/farmacología , Proteínas tau/metabolismo , Fosforilación , Ratas Wistar , Isquemia Encefálica/tratamiento farmacológico , Isquemia , Reperfusión , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Fármacos Neuroprotectores/farmacologíaRESUMEN
Late onset Alzheimer´s disease (AD) is a neurodegenerative disease with gender differences in its onset and progression, being the prevalence predominant in women and at an earlier age than in men. The pathophysiology of the menopausal condition has been associated to this dementia, playing major roles regarding both endocrine and glucose metabolism changes, amongst other mechanisms. In the current review we address the role of estrogen deficiency in the processes involved in the development of AD, including amyloid precursor protein (APP) processing to form senile plaques, Tau phosphorylation forming neurofibrillary tangles, Wnt signaling and AD neuropathology, the role of glucose brain metabolism, Wnt signaling and glucose transport in the brain, and our research contribution to these topics.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Masculino , Femenino , Humanos , Enfermedad de Alzheimer/metabolismo , Proteínas tau , Enfermedades Neurodegenerativas/metabolismo , Vía de Señalización Wnt , Menopausia , GlucosaRESUMEN
Alzheimer's Disease (AD) is the most common cause of dementia. AD patients had increased extracellular amyloid ß plaques and intracellular hyperphosphorylated tau (p-tau) in neurons. Recent studies have shown an association between the Renin-Angiotensin System (RAS) and AD. The involvement of RAS has been mediated through Angiotensin II (AngII), which is overexpressed in aging brains. However, the exact mechanism of how AngII contributes to AD is unknown. Thus, we hypothesize that AngII increases p-tau by activating its kinases, CDK5 and MAPK. In the human cortical neuron cell line, HCN2, treatment with AngII upregulated the gene expression of CDK5 (2.9 folds, p < 0.0001) and MAPTK (1.9 folds, p < 0.001). The AT1R antagonist, Losartan, blocked the changes in tau kinases. Also, AngII-induced the MAPK activation, increasing its phosphorylation by 400% (p < 0.0001), an increase that was also blocked by Losartan. An increase in p-tau by AngII was observed using fluorescent microscopy. We then quantified Reactive Oxygen Species (ROS) production, and it was significantly increased by AngII (p < 0.01), and treatment with Losartan blunted their production (p < 0.05). The data obtained demonstrated that AngII might contribute to the pathogenesis of AD.
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1-(7-Chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) is a new multi-target directed ligand (MTDL) rationally designed to have affinity with ß-secretase (BACE), Glycogen Synthase Kinase 3ß (GSK3ß) and acetylcholinesterase, which are considered promising targets on the development of disease-modifying therapies against Alzheimer's Disease (AD). Previously, QTC-4-MeOBnE treatment showed beneficial effects in preclinical AD-like models by influencing in vivo neurogenesis, oxidative and inflammatory pathways. However, the biological effect and mechanism of action exerted by QTC-4-MeOBnE in AD cellular models have not been elucidated yet. Hereby we investigate the acute effect of QTC-4-MeOBnE on neuronal cells overexpressing Amyloid Protein Precursor (APP) or human tau protein, the two main features of the AD pathophysiology. When compared to the control group, QTC-4-MeOBnE treatment prevented amyloid beta (Aß) formation through the downregulation of APP and BACE levels in APPswe-expressing cells. Furthermore, in N2a cells overexpressing human tau, QTC-4-MeOBnE reduced the levels of phosphorylated forms of tau via the modulation of the GSK3ß pathway. Taken together, our findings provide new insights into the mechanism of action exerted by QTC-4-MeOBnE in AD cellular models, and further support its potential as an interesting therapeutic strategy against AD.
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Enfermedad de Alzheimer , Proteínas tau , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Fosforilación , Quinolinas , Triazoles/uso terapéutico , Proteínas tau/metabolismoRESUMEN
The cellular processes regulated by WNT signaling have been mainly studied during embryonic development and cancer. In the last two decades, the role of WNT in the adult central nervous system has been the focus of interest in our laboratory. In this chapter, we will be summarized ß-catenin-dependent and -independent WNT pathways, then we will be revised WNT signaling function at the pre- and post-synaptic level. Concerning Alzheimer's disease (AD) initially, we found that WNT/ß-catenin signaling activation exerts a neuroprotective mechanism against the amyloid ß (Αß) peptide toxicity. Later, we found that WNT/ß-catenin participates in Tau phosphorylation and in learning and memory. In the last years, we demonstrated that WNT/ß-catenin signaling is instrumental in the amyloid precursor protein (APP) processing and that WNT/ß-catenin dysfunction results in Aß production and aggregation. We highlight the importance of WNT/ß-catenin signaling dysfunction in the onset of AD and propose that the loss of WNT/ß-catenin signaling is a triggering factor of AD. The WNT pathway is therefore positioned as a therapeutic target for AD and could be a valid concept for improving AD therapy. We think that metabolism and inflammation will be relevant when defining future research in the context of WNT signaling and the neurodegeneration associated with AD.
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Enfermedad de Alzheimer , Vía de Señalización Wnt , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Humanos , FosforilaciónRESUMEN
Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-ß peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.
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Astrocitos/patología , Microglía/patología , Enfermedades Neurodegenerativas/patología , Schistosoma mansoni/aislamiento & purificación , Esquistosomiasis mansoni/complicaciones , Acetilcisteína/farmacología , Animales , Antihelmínticos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Deferoxamina/farmacología , Modelos Animales de Enfermedad , Depuradores de Radicales Libres/farmacología , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiología , Praziquantel/farmacología , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/metabolismo , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/patología , Sideróforos/farmacologíaRESUMEN
Alzheimer's disease (AD) is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-ß (Aß) peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aß toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein (APP) processing and that Wnt dysfunction results in Aß production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic (Tg) mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aß formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aß1-42 production in the hippocampus of wild-type (WT) mice, contributing to the development of an Alzheimer's-like neurophatology. Therefore, in this review we highlight the importance of Wnt/ß-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
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Sex differences are important to consider when studying different psychiatric, neurodevelopmental, and neurodegenerative disorders, including Alzheimer's disease (AD). These disorders can be affected by dimorphic changes in the central nervous system and be influenced by sex-specific hormones and neuroactive steroids. In fact, AD is more prevalent in women than in men. One of the main characteristics of AD is the formation of neurofibrillary tangles, composed of the phosphoprotein Tau, and neuronal loss in specific brain regions. The scope of this work is to review the existing evidence on how a set of hormones (estrogen, progesterone, and prolactin) affect tau phosphorylation in the brain of females under both physiological and pathological conditions.
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Wnt signaling plays an important role in the adult brain function and its dysregulation has been implicated in some neurodegenerative pathways. Despite the functional role of the Wnt signaling in adult neural circuits, there is currently no evidence regarding the relationships between exogenously Wnt signaling activation or inhibition and hippocampal structural changes in vivo. Thus, we analyzed the effect of the chronic infusion of Wnt agonists, Wnt7a and Wnt5a, and antagonist, Dkk-1, on different markers of plasticity such as neuronal MAP-2, Tau, synapse number and morphology, and behavioral changes. We observed that Wnt7a and Wnt5a increased the number of perforated synapses and the content of pre-and postsynaptic proteins associated with synapse assembly compared to control and Dkk-1 infusion. These two Wnt agonists also reduced anxiety-like behavior. Conversely, the canonical antagonist, Dkk-1, increased anxiety and inhibited spatial memory recall. Therefore, the present study elucidates the potential participation of Wnt signaling in the remodeling of hippocampal circuits underlying plasticity events in vivo, and provides evidence of the potential benefits of Wnt agonist infusion for the treatment of some neurodegenerative conditions.
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Ansiedad/terapia , Hipocampo/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Memoria/efectos de los fármacos , Proteínas Wnt/uso terapéutico , Proteína Wnt-5a/uso terapéutico , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/ultraestructura , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Neuroblastoma/patología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/ultraestructura , Proteínas Wnt/ultraestructura , Proteína Wnt-5a/ultraestructuraRESUMEN
Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are histological markers of Alzheimer's disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. Okadaic acid (OKA), a strong inhibitor of protein phosphatase 2A, has been used to induce dementia similar to AD in rats. We herein investigated the effect of intracerebroventricular (ICV) infusion of OKA (100 and 200ng) on hippocampal tau phosphorylation at Ser396, which is considered an important fibrillogenic tau protein site, and on glucose uptake, which is reduced early in AD. ICV infusion of OKA (at 200ng) induced a spatial cognitive deficit, hippocampal astrogliosis (based on GFAP increment) and increase in tau phosphorylation at site 396 in this model. Moreover, we observed a decreased glucose uptake in the hippocampal slices of OKA-treated rats. In vitro exposure of hippocampal slices to OKA altered tau phosphorylation at site 396, without any associated change in glucose uptake activity. Taken together, these findings further our understanding of OKA neurotoxicity, in vivo and vitro, particularly with regard to the role of tau phosphorylation, and reinforce the importance of the OKA dementia model for studying the neurochemical alterations that may occur in AD, such as NFTs and glucose hypometabolism.
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Inhibidores Enzimáticos/administración & dosificación , Glucosa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ácido Ocadaico/administración & dosificación , Animales , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Glutamato-Amoníaco Ligasa/metabolismo , Ácido Glutámico/metabolismo , Glutatión/metabolismo , Técnicas In Vitro , Inyecciones Intraventriculares , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Subunidad beta de la Proteína de Unión al Calcio S100/líquido cefalorraquídeo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Proteínas tau/metabolismoRESUMEN
Leishmaniasis is a parasitosis caused by several species of the genus Leishmania, an obligate intramacrophagic parasite. Although neurologic symptoms have been observed in human cases of leishmaniasis, the manifestation of neurodegenerative processes is poorly studied. The aim of the present work was to investigate if peripheral infection of BALB/c mice with Leishmania amazonensis affects tau phosphorylation and RAGE protein content in the brain, which represent biochemical markers of neurodegenerative processes observed in diseases with a pro-inflammatory component, including Alzheimer's disease and Down syndrome. Four months after a single right hind footpad subcutaneous injection of L. amazonensis, the brain cortex of BALB/c mice was isolated. Western blot analysis indicated an increase in tau phosphorylation (Ser(396)) and RAGE immunocontent in infected animals. Brain tissue TNF-α, IL-1ß, and IL-6 levels were not different from control animals; however, increased protein carbonylation, decreased IFN-γ levels and impairment in antioxidant defenses were detected. Systemic antioxidant treatment (NAC 20mg/kg, i.p.) inhibited tau phosphorylation and recovered IFN-γ levels. These data, altogether, indicate an association between impaired redox state, tau phosphorylation and RAGE up-regulation in the brain cortex of animals infected with L. amazonensis. In this context, it is possible that neurologic symptoms associated to chronic leishmaniasis are associated to disruptions in the homeostasis of CNS proteins, such as tau and RAGE, as consequence of oxidative stress. This is the first demonstration of alterations in biochemical parameters of neurodegeneration in an experimental model of Leishmania infection.
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Encéfalo/parasitología , Leishmania mexicana , Leishmaniasis/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas tau/metabolismo , Animales , Encéfalo/metabolismo , Citocinas/metabolismo , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/fisiología , Fosforilación , Receptor para Productos Finales de Glicación Avanzada , Regulación hacia ArribaRESUMEN
The abnormal phosphorylation of the microtubule-associated protein tau is a prominent aspect of Alzheimer's disease (AD). Considerable evidence suggests that glycogen synthase kinase 3ß (GSK3ß) and the protein phosphatase 2A (PP2A) are involved in normal and pathological tau phosphorylation. However, the mechanisms underlying a shift of the phosphorylation/dephosphorylation balance that leads to abnormal tau phosphorylation remains unknown. The canonical Wnt pathway negatively regulates GSK3ß activity, and this signaling pathway has also been found to be dysregulated in the AD brain. Here, we report that the Wnt antagonist Dkk-1 selectively increases tau phosphorylation in the hippocampus of aged rats at Ser199/202, Ser396/404, and Ser214 sites. In the aged hippocampus, the inhibition of Wnt signaling is also accompanied by reduced PP2A activity. This study suggests that aging promotes tau hyperphosphorylation after Wnt inhibition, due to an imbalance between GSK3ß and PP2A activities.